The successful use of mesenchymal stem cells to treat steroid-resistant severe graft-versus-host disease (GVHD) was a milestone in regenerative medicine (Le Blanc et al., Lancet, 2004). Since those initial reports were published, multiple clinical trials have been initiated to test MSC treatment of GVHD, Crohn's disease, ulcerative colitis and multiple sclerosis (Le Blanc et al., Nature Reviews Immunology, 2012). This broad applicability is an implication of the ability of MSCs to modulate nearly every cellular component of the innate and adaptive immune system. This includes reducing inflammation and neutrophil activation, modulating macrophages towards an anti-inflammatory phenotype, inhibiting NK cell activation and cytotoxicity, modulating dendritic cell activation, as well as modulating CD4+ and CD8+ T cell responses (Selmani et al., Stem Cells, 2008).
Concurrently, costimulation blockade has emerged as a promising strategy for replacing immunity with tolerance. In a seminal article from 1996, it was demonstrated that by blocking B7 and CD40L with CTLA4Ig and anti-CD40L in the peri-operative period, indefinite survival of vascularised allografts could be achieved (Larsen et al., Nature, 1996). Inhibition of costimulatory signals, while allowing for TCR/MHC interactions to remain intact, renders T cells anergic to donor antigen. In later studies, tolerance toward the transplants was shown to be in part due to the development of intra-graft Foxp3+ regulatory T cells generated specifically towards donor antigen with the ability to specifically inhibit anti-donor immune responses.
Later studies would show however that this was not universal to all transplant models and heterologous immunity, cross-reactivity of memory T cells to donor antigen, will probably be a major barrier in a clinical setting.
Studies in mice indicate that tolerance can be induced efficiently using one or more costimulation inhibitors but translation into non-human primates and humans has not been without obstacles, due to the complexities of e.g. the human immune system. For instance, certain subsets of T cells such as memory T cells, which have a reduced reliance on costimulation pathways, are relatively resistant to treatment with the costimulation blockade, leading to e.g. increased incidence of transplant rejection (Kinnear et al., Transplantation, 2013)). Furthermore, it is noteworthy that the development of novel reagents for modulating the costimulation pathway has resulted in severe adverse events, for instance cytokine storms, etc.
Costimulation blockade and MSC treatment modulate many of the same components of the immune system and can induce the peripheral conversion of T cells to a regulatory T cells. These two treatment strategies are being tested independently in clinical organ transplantation with the hope of improving graft function and recipient survival but because these strategies converge on some of the same targets the two approaches have traditionally been seen as mutually exclusive. This therapeutic similarity is evidenced by a study by Sullivan and coworkers (Sullivan et al., Stem Cells Dev, 2013), wherein MSCs that were genetically modified to express CTLA4Ig failed to augment the immunosuppressive effects of unmodified MSCs when treating mice with collagen-induced arthritis.